The endocytosis of proteins by the proximal tubule is mediated by apical membrane proteins that specifically bind proteins and peptides in tubule fluid. These receptors, called multiligand endocytic receptors, can bind a wide range of peptides and proteins and thereby mediate their endocytosis. Megalin and cubilin mediate protein and peptide endocytosis in the proximal tubule. Both are glycoproteins, with megalin being a member of the low-density lipoprotein receptor gene family.
Fig. 34.5 illustrates the mechanisms of organic anion (OA−) transport across the proximal tubule. These secretory pathways have maximum transport rates, low specificity (i.e., they transport many OA−s), and are responsible for secretion of the OA−s listed in
Box 34.1.
OA−s are taken up into the cell across the basolateral membrane against their chemical gradient in exchange for α-ketoglutarate (α-KG) via several OA−/α-KG antiporters, including OAT1, OAT2, and OAT3. α-KG accumulates inside the cells via metabolism of glutamate and by a Na+/α-KG symporter (i.e., the Na+/dicarboxylate transporter [NaDC3]) also present in the basolateral membrane. Thus uptake of OA− into the cell against an electrochemical gradient is coupled to the
Urinalysis is an important and routine tool for detection of kidney disease. A thorough analysis of urine includes macroscopic, microscopic, and biochemical assessments. This is performed by visual assessment of the urine, microscopic examination of urinary sediment, and biochemical evaluation of urinary composition using dipstick reagent strips. The dipstick test is both inexpensive and fast (i.e., <5 minutes) and tests urine for both pH and the presence of many substances (e.g., bilirubin, blood, glucose, ketones, protein). It is normal to find trace amounts of protein in urine, particularly concentrated urine. Urinary proteins are derived from two principal sources: (1) filtration exceeding the reabsorptive capacity of the proximal tubule and (2) synthesis and secretion of Tamm-Horsfall glycoprotein by the thick ascending limb of Henle’s loop. Because the mechanism for protein reabsorption is “upstream” of the thick ascending limb (i.e., in the proximal tubule), the secreted Tamm-Horsfall glycoprotein appears in urine. However, proteinuria in greater than trace amounts is often indicative of renal disease.
exit of α-KG out of the cell, down its chemical gradient generated by the Na+/α-KG symporter mechanism. The exit of OA−s across the luminal membrane into the tubular fluid are mediated by multidrug resistance proteins 2 and 4 (MRP2/4) and breast cancer resistance protein 1 (BCRP), which require adenosine triphosphate (ATP) for their operation. Recent studies reveal that OAT4 mediates reabsorption of the organic anion urate, the end product of purine catabolism, by the proximal tubule (see
Fig. 34.5 •Fig. 34.6 Organic cation (OC+) secretion across the proximal tubule. OC+s enter the cell across the basolateral membrane primarily by OCT2. Uptake of OC+s into the cell against their chemical concentration gradient is driven by the cell-negative potential difference. OC+s leave the cell across the apical membrane in exchange with H+by electrically neutral multidrug and toxin transporters (MATE1 and MATE2-K) and by multidrug resistance protein (MDR1), which requires ATP. ATP OCT2MATE MDR1 Na+ OC+ OC+ H+ K+ Blood Tubular fluid OC+ ATP ADP